Clinical Use

Assess risk for coronary heart disease (CHD; primary or secondary)
Monitor nondrug or drug therapy
Clinical Background

Low-density lipoprotein-cholesterol (LDL-C) testing is an important part of a CHD prevention strategy. It is used to assess the risk of CHD and also to monitor patients who have an increased risk of CHD due to prior CHD, other atherosclerotic disease(s), diabetes mellitus, or other risk factors. The risk of CHD can be reduced through lifestyle changes and medical therapy.1-3 Alternative pharmacotherapy may be recommended if statins are not tolerated or insufficiently lower LDL-C.2,3

LDL-C is recommended as a primary target of lipid-lowering therapy for CHD prevention.2,3 However, approaches to LDL-C monitoring during therapy vary. A 2018 multi-organization guideline recommends targeting percent reductions in LDL-C from baseline.2 Alternatively, guidelines from the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) recommend targeting absolute LDL-C values.3 In both guidelines, LDL-C targets depend on a patient’s atherosclerotic cardiovascular disease (ASCVD) risk, and absolute LDL-C values are used as thresholds for therapy intensification.2,3 Regardless of the guidelines followed, accurate measurement of LDL-C is important for patient management.

Because of the complexity of direct measurement, LDL-C levels have traditionally been calculated using the Friedewald equation4:

LDL-C (mg/dL) = total cholesterol – HDL-C – TG/5

This equation is based on 3 separate measurements: total cholesterol (the sum of all forms of cholesterol, including very low-density lipoprotein-cholesterol [VLDL-C]), high-density lipoprotein-cholesterol (HDL-C), and triglycerides (TG). “TG/5” is an estimate of VLDL-C. The fixed factor of 5 represents a presumed “constant” ratio of TG to VLDL-C cholesterol, which was originally derived from a sample of 448 people in the early 1970s.4 This approach has some limitations. Specifically, for patients with high TG and/or low LDL-C levels, the equation may yield artificially high VLDL-C and artificially low or non-reportable LDL-C values.

Therefore, Quest Diagnostics calculates LDL-C using an alternative method that allows greater personalization to a patient’s specific TG level: the Martin-Hopkins calculation.5 The Martin-Hopkins calculation uses an adjustable factor to estimate VLDL-C instead of a fixed factor of 5, but is otherwise similar to the Friedewald equation. This adjustable factor was derived from an analysis of TG to VLDL-C ratios in nearly 1.4 million people.5 The factor is chosen from a matrix table of 180 possible factors, which range from 3.1 to 11.9, corresponding to an individual’s TG and non-HDL-C (total cholesterol – HDL-C) levels. It is lowest (3.1) for patients with very low levels of TG (7 to 49 mg/dL) and high levels of non-HDL-C (≥220 mg/dL), and highest (11.9) for those with very high levels of TG (≥400 mg/dL) and low levels of non-HDL-C (<100 mg/dL).

Compared with the Friedewald equation, the Martin-Hopkins calculation provides better correlation with direct LDL-C measurements.5-9 Concordance with guidelines-based risk classification, especially at high TG and low LDL-C, is also superior using the Martin-Hopkins calculation.5-9 Importantly, total atherogenic burden, assessed by apolipoprotein B and non-HDL-C levels, tracks more closely with LDL-C using the Martin-Hopkins calculation.10 The ability of the Martin-Hopkins calculation to adjust for high TG levels may also make LDL-C estimation more reliable in nonfasting patients.11 This can be convenient for risk assessment, especially for patients who have difficulty fasting (eg, young children and people with diabetes).11 The improved accuracy at lower LDL-C (≤70 mg/dL) allows more accurate categorization of patients in very high-risk categories undergoing aggressive treatment with low LDL-C goals.

Assays with calculated LDL-C include Lipid Panel (test codes 7600 and 91716), ASCVD Risk Panel with Score (test codes 92053 and 92052), Lipid Panel with Reflex to Direct LDL (test codes 14852 and 92061), and Lipid Panel with Ratios (test code 19543). Panel components can be ordered separately (total cholesterol [test codes 334 and 91717], HDL-C [test codes 608 and 91719], and TG [test codes 896 and 91718]).

The direct LDL-C assay (test codes 8293 and 91723) provides an alternative to calculated LDL-C. Direct measurement provides a reliable result even when TG levels are up to 1,290 mg/dL, or LDL-C values are low (10 to 40 mg/mL) and calculation is less accurate.8 Further, the direct LDL-C assay has been correlated with the CDC-accepted reference method (“the gold standard”). Thus, results can be related to the epidemiologic data that have been generated for the assessment of CHD risk and the monitoring of therapy to reduce that risk.

Individuals Suitable for Testing

Individuals undergoing cardiovascular disease (CVD) risk assessment
Individuals at intermediate CVD risk who are being considered for pharmacotherapy
Individuals undergoing LDL-C-lowering pharmacotherapy
Method

Calculated LDL-C
Enzymatic assays for total cholesterol, HDL-C, and TG
Adjustable factors read from a 180-cell table based on TG and non-HDL-C are used for calculating VLDL-C, and subsequently LDL-C5
Direct LDL-C
Two-phase enzymatic: enzymatic assay for LDL-C after selectively solubilizing and enzymatically digesting non-LDL-lipoproteins
Analytical measurement range: 10 to 400 mg/dL
Interpretive Information

Target LDL-C levels vary by guideline. The AACE/ACE guideline recommends the following LDL-C goals for patients: <55 mg/dL for those with extreme risk (eg, premature ASCVD); <70 mg/dL for those with very high risk (eg, ASCVD or diabetes); <100 mg/dL for those with high or moderate risk; and <130 mg/dL for those with low risk.3 The multi-organization guideline recommends reductions from baseline of ≥30% to ≥50%, depending on patient characteristics, risk assessment, and therapy.2 Once lipid goals have been achieved, guidelines recommend follow-up testing every 3 to 12 months.2,3

Patients with very high LDL-C (≥190 mg/mL) are at risk for familial hypercholesterolemia.3"

Includes
Cholesterol, Total
Triglycerides
HDL Cholesterol
LDL-Cholesterol (calculated)
Cholesterol/HDL Ratio (calculated)
Non-HDL Cholesterol (calculated)

Patient Preparation
Fasting is not required prior to collection of a lipid panel.
The assay manufacturer Beckman Coulter advises: "N-Acetyl Cysteine (NAC), when administered in therapeutic concentrations (for the treatment of acetaminophen overdose), has been. . . determined to interfere with assays for. . . cholesterol, uric acid" where "NAC interference may lead to falsely low results." According to Beckman Coulter, the NAC interference should be insignificant by 12 hours after completion of the initial loading dose of an IV infusion treatment regimen consisting of an initial loading dose of 150 mg/kg administered over 1 hour, a second dose of 50 mg/kg administered over 4 hrs and a third dose of 100 mg/kg administered over 16 hrs.

Methodology
Spectrophotometry (SP)

Reference Range(s)

Total Cholesterol    Male
(mg/dL)    Female
(mg/dL)
<20 Years    <170    <170
≥20 Years    <200    <200
HDL Cholesterol          
<20 Years    >45    >45
≥20 Years    ≥40    ≥50
Triglycerides          
≤9 Years    <75    <75
10-19 Years    <90    <90
≥20 Years    <150    <150
           
LDL-Cholesterol (calc)          
<20 Years    <110    <110
≥20 Years    <100    <100
Cholesterol/HDL Ratio (calc)    <5.0    <5.0
Non-HDL Cholesterol (calc)          
<20 Years    <120    <120
≥20 Years    <130    <130

Alternative Name(s)
Standard Lipid Panel,Martin Hopkins calculation,Non-fasting Lipid Panel